Tension-free sub-urethral tapes have revolutionized the surgical treatment of female stress urinary incontinence for the past decade. The inside-out transobturator approach, developed in our Institution 5 years ago, is currently being utilized worldwide. The technique is simple and reproducible and the incidence of complications is minimized. Stress urinary incontinence cure rates of almost 90% are achieved after a 3-year minimum follow up. These good results have been confirmed in the international literature. [less ▲]

Introduction: The best outcome for patients with prostate cancer (PCa) is seen for those treated at an early stage of the disease. A digital rectal examination (DRE) and the measurement of serum prostate ... [more ▼]

Introduction: The best outcome for patients with prostate cancer (PCa) is seen for those treated at an early stage of the disease. A digital rectal examination (DRE) and the measurement of serum prostate specific antigen (PSA) levels are the current standards for PCa early detection. However, serum PSA testing lacks both sensitivity and specificity, and core biopsies frequently fail to identify small foci of PCa. The availability of non-invasive diagnostic molecular tests that could allow for a more precise identification of malignant prostate cells in asymptomatic men would be of great clinical value to improve PCa diagnosis. Study design: 114 men scheduled to undergo a prostate biopsy were enrolled in the study. The biopsies were triggered either by an abnormally high PSA value or by suspicious findings on DRE. Patients with other known or suspected urinary malignancy were excluded from the study. Morning, post-prostate massage and post-biopsy urine samples were collected from all individuals. The main goals of this study were a) to determine if prostate massage can improve the prostate DNA quantity compared to urine collected in the morning or after biopsy, and b) to evaluate the methylation status of a gene panel in urine samples from subjects with cancer found in prostate biopsy tissue cores versus subjects without cancer. Methods: Gene promoter methylation is associated with prostate cancer and has been successfully used for the molecular detection of neoplasia in urine. We have developed real-time methylation specific PCR assays to define the methylation status of several genes. Results: Median age of the patients was 65 years (range 48-85). PCa was found in 51% of the patients. Histological diagnosis of the biopsies was compared to methylation results in urine from 102 samples (89% success rate due low DNA yields for 12 samples). The comparison between different urine sampling techniques showed that prostate massage is needed. The best results were obtained in post massage urine samples with a combination of GSTP1, p14, p16, RARβ2 and RASSF1A resulting in a sensitivity of 74% and a specificity of 75%. Future: A multiplex assay using the Cepheid SmartCycler™ II platform is under development. Further studies are in progress to validate the assay across multiple centers. [less ▲]

A promising avenue toward the development of more selective anticancer drugs consists in the targeted delivery of bioactive molecules to the tumor environment by means of binding molecules specific to ... [more ▼]

A promising avenue toward the development of more selective anticancer drugs consists in the targeted delivery of bioactive molecules to the tumor environment by means of binding molecules specific to tumor-associated markers. We have used a chemical proteomics approach based on the ex vivo perfusion and biotinylation of accessible structures within surgically resected human kidneys with tumor to gain information about accessible and abundant antigens that are overexpressed in human cancer. This procedure led to the selective labeling with biotin of vascular structures. Biotinylated proteins were purified on streptavidin resin and identified using mass spectrometric methodologies, revealing 637 proteins, 184 of which were only found in tumor specimens and 223 of which were only found in portions of normal kidneys. Immunohistochemical and PCR analysis confirmed that several of the putative cancer antigens identified in this study are indeed preferentially expressed in tumors. In conclusion, we have developed a methodology that allows the identification of accessible biomarkers in human tissues. The tumor-associated antigens identified in this study may be suitable targets for antibody-based anticancer therapies. The experimental approach described here should be applicable to other surgical specimens and to other pathologies as well as to the study of basic physiological and immunological processes. [less ▲]

OBJECTIVE: We investigated the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa). METHODS: Expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and TXA(2) receptors (TPRs), the main actors of the TXA(2) pathway, was analyzed on serial tissue sections from 46 human PCa specimens. RESULTS: The expression levels of COX-2, TXS, and TPRs were significantly higher in malignant than in corresponding nontumoral prostatic epithelial cells. Increased immunoreactivity for these antigens was also observed in high-grade prostate intraepithelial neoplasia (HGPIN) glands. COX-2, TXS, and TPR proteins usually displayed a coordinated overexpression pattern in PCa lesions, as assessed in serial tissue sections. Increased levels of these proteins in the tumors were all significantly associated with higher Gleason scores and pathologic stages. CONCLUSIONS: Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. Our study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy. [less ▲]

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A ... [more ▼]

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor ( VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 mu M. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca2+ pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11- dideoxy- 9,11- methanoepoxyprostaglandin F 2) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl] urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2p- toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration. [less ▲]

Histopathological studies of gastrointestinal motility disorders have mainly focused on enteric nerves and interstitial cells of Cajal, but rarely considered the enteric musculature. Here we used both ... [more ▼]

Purpose: We analyzed the results of a prospective, observational trial designed to assess the safety and efficacy of the TVT-O procedure for female SUI. Materials and Methods: Preoperative and ... [more ▼]

Purpose: We analyzed the results of a prospective, observational trial designed to assess the safety and efficacy of the TVT-O procedure for female SUI. Materials and Methods: Preoperative and postoperative evaluations included physical examination, and urinary symptom and quality of life scale questionnaires. Results: Between March 2003 and December 2004, 253 patients with clinical and urodynamic diagnoses of SUI who fulfilled inclusion and exclusion criteria were enrolled in the trial and underwent the TVT-O procedure. No significant intraoperative complications were observed. One-year minimum followup was available on 99 of the initial 102 patients, of whom 16 had undergone concomitant pelvic organ prolapse surgical treatment. The SUI complete cure rate was 91%. No patient had vaginal or urethral erosion. Four patients required tape release or section. Frequency and urge symptoms improved after the operation (p < 0.001). The severity of obstructive symptoms slightly increased postoperatively in the group of patients who did not undergo associated pelvic organ prolapse treatment (p < 0.05), while maximum flow rates somewhat decreased (p < 0.001) and post-void residual urine volumes somewhat increased (p < 0.005). Most patients reported a significant decrease in incontinence severity and improvement in quality of life (p < 0.0001). Conclusions: The results of this study, which suggest that the TVT-O procedure is a safe and efficient surgical treatment for female SUI, warrant further comparative evaluation of this procedure with retropubic and outside in transobturator approaches in appropriately designed, prospective, randomized trials. [less ▲]

PURPOSE: To investigate early prostate-specific antigen (PSA) kinetics after high radiation doses of 85 Gy on locally advanced prostate cancer. METHODS AND MATERIALS: A total of 201 patients were ... [more ▼]

PURPOSE: To investigate early prostate-specific antigen (PSA) kinetics after high radiation doses of 85 Gy on locally advanced prostate cancer. METHODS AND MATERIALS: A total of 201 patients were prospectively and consecutively treated with external beam radiotherapy and a brachytherapy boost. Of the 201 patients, 104 received concomitant hormonal therapy on the decision of the referring urologist and were excluded, yielding a study population of 97 patients. The first posttreatment PSA analysis was performed not earlier than 1 month after treatment completion but within the first 4 months, and then every 4 months. Analysis of PSA kinetics included the PSA nadir (nPSA) at values of < or =4 ng/mL to < or =0.5 ng/mL. The nPSA at < or =4 ng/mL within 4 months (nPSA < or =4/4m) was the variable of interest. RESULTS: We established highly significant associations between an nPSA of < or =1 and < or =0.5 ng/mL and the nPSA < or =4/4m (p <0.0001). A hazard ratio of 0.33 (95% Confidence Interval (CI), 0.12-0.91) underlined the lower risk of recurrence related to nPSA < or =4/4m achievement (p = 0.033). Using time-dependent covariate models for patients who did not reach an nPSA < or =4/4m, an nPSA of < or =1 ng/mL remained without prognostic significance (p = 0.06). However, for patients who reached an nPSA < or =4/4m, an nPSA of < or =1 ng/mL did significantly improve the prognosis (p <0.001), but much later after treatment. The same analysis was repeated for nPSA < or =0.5 ng/mL with similar conclusions as when nPSA < or =4/4m was obtained (p <0.01). CONCLUSION: The nPSA < or =4/4m has been demonstrated to be a significant predictor of biochemical no evidence of disease after high radiation doses of 85 Gy. Its major advantage is that it was available earlier than the other nadirs. [less ▲]

Uterine smooth muscle tumors (SMTs) are usually recognized on the basis of their routine morphologic features; however, their distinction from endometrial stromal tumors (ESTs), the second most common ... [more ▼]

Uterine smooth muscle tumors (SMTs) are usually recognized on the basis of their routine morphologic features; however, their distinction from endometrial stromal tumors (ESTs), the second most common mesenchymal tumor of the uterus, is sometimes problematic. Histone deacetylases (HDACs) were originally identified as nuclear enzymes regulating histone acetylation. We have recently shown that in normal human tissues, HDAC8 is exclusively expressed in the cytoplasm of cells showing smooth muscle differentiation. In this study, we examined HDAC8 expression in SMTs and ESTs of the uterus to determine whether HDAC8 may be a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors. HDAC8 immunohistochemical staining was performed in 15 leiomyomas (LMs), 9 highly cellular leiomyomas (HCLs), 8 epithelioid SMTs, 13 leiomyosarcomas (LMSs), and 17 ESTs, including 3 with sex-cord differentiation and 5 with smooth muscle differentiation. All tumors were also stained for other smooth muscle markers (desmin, h-caldesmon, smooth muscle actin [SMA], smooth muscle myosin heavy chain) and for CD 10. All LMs had moderate to strong expression of all smooth muscle markers. HDAC8 was detected in 8 of 9 HCLs and in all epithelioid SMTs (8 of 8); however, it was weak in 4 epithelioid SMTs. In contrast, desmin, h-caldesmon and smooth muscle myosin were positive in only 2 of 8, 1 of 8 and 4 of 8 epithelioid SMTs, respectively. All smooth muscle markers had similar frequency of staining in LMSs; however, HDAC8 showed overall moderate intensity compared with other smooth muscle markers, which showed stronger staining. HDAC8, h-caldesmon, and smooth muscle myosin did not stain conventional areas of ESTs or ESTs with sex-cord differentiation, whereas SMA and desmin were positive in those areas in 4 of 12 and 3 of 12 ESTs, respectively. Areas of smooth muscle differentiation in ESTs were positive for HDAC8 in all cases, but they were less constantly positive for the other smooth muscle markers. CD10 was expressed in most ESTs (14 of 17), but it was also positive in 15 of 45 SMTs. In conclusion: 1) HDAC8 seems to be a specific marker of SM differentiation because conventional ESTs and ESTs with sex-cord differentiation are negative for HDAC8, whereas areas of smooth muscle differentiation in these tumors are consistently positive; 2) HDAC8 gives similar results to those obtained with desmin, h-caldesmon, and smooth muscle myosin in both LMs and LMSs, although the staining for HDAC8 in LMSs tends to be less intense; 3) HDAC8 may be a more sensitive marker than desmin and h-caldesmon in epithelioid SMTs. Thus, HDAC8 detection may be useful in helping the differential diagnosis of uterine mesenchymal tumors. [less ▲]

in International Journal of Cancer = Journal International du Cancer (2006), 118(4), 850-856

Recent studies have demonstrated that two SIBLING family members, bone sialoprotein (BSP) and osteopontin (OPN), are overexpressed in human prostate cancer. The expression of these proteins is associated ... [more ▼]

Recent studies have demonstrated that two SIBLING family members, bone sialoprotein (BSP) and osteopontin (OPN), are overexpressed in human prostate cancer. The expression of these proteins is associated with the acquisition of a metastatic phenotype by cancer cells and a poor prognosis for the patient. Dentin sialophosphoprotein (DSPP) shares several structural and genetic features with OPN and BSP. The presence of DSPP has been recently established in salivary glands, indicating that its expression is not restricted to mineralized tissues. However, its potential expression in human tumors has not been addressed yet. In this study, we sought to evaluate the expression of DSPP in human prostate cancer. Immunohistochemistry was performed on 69 prostate cancer specimens using LFMb-21 anti-DSPP monoclonal antibody. All of the prostate cancer lesions examined expressed detectable levels of DSPP, as compared with no or low level of expression in adjacent normal glands (p < 0.0001). High grade prostatic intraepithelial neoplasia (HGPIN) glands generally displayed DSPP expression levels that were similar to those found in neighboring cancer glands. DSPP expression was significantly associated with the pathological stage (p = 0.0087) and the Gleason score (p = 0.0176) of the tumors. Western Blot was performed on 5 representative prostate tumor extracts and 3 prostatic tumor cell lines (PC3, LNCaP and DU145). All tumor extracts and cell lines analyzed have been found to express DSPP. In addition, in situ hybridization was used to assess the presence of DSPP mRNA. DSPP was detected at the RNA level in both HGPIN and tumoral glands. This study shows for the first time that DSPP is ectopically expressed in human prostate cancer. The expression of this SIBLING protein strongly correlates with conventional histopathological prognostic indicators of prostate cancer progression. (c) 2005 Wiley-Liss, Inc. [less ▲]